HIF-hypoxia signaling in skeletal muscle physiology and fibrosis

Hypoxia refers to the decrease in oxygen tension in the tissues, and the central effector of the hypoxic response is the transcription factor Hypoxia-Inducible Factor alpha (HIF1-alpha). Transient hypoxia in acute events, such as exercising or regeneration after damage, play an important role in skeletal muscle physiology and homeostasis. However, sustained activation of hypoxic signaling is a feature of skeletal muscle injury and disease, which can be a consequence of chronic damage but can also increase the severity of the pathology and worsen its outcome. Here, we review evidence that supports the idea that hypoxia and HIF-1 alpha can contribute to the establishment of fibrosis in skeletal muscle through its crosstalk with other profibrotic factors, such as Transforming growth factor beta (TGF-beta), the induction of profibrotic cytokines expression, as is the case of Connective Tissue Growth Factor (CTGF/CCN2), or being the target of the Renin-angiotensin system (RAS).